Wednesday, October 17, 2007

Etanercept for cachexia; Pathologic fracture prognosis; "Euthanasia" understanding; & more

A few articles from recent issues of Cancer, and a couple of other things as well....

Cancer recently published the results of a randomized, placebo controlled trial of etanercept for cancer cachexia. Etanercept (Enbrel) is a tumor necrosis factor (TNF)-alpha inhibitor which is used for rheumatoid arthritis. Since there's good reason to believe cancer anorexia/cachexia is mediated, in part, by inflammatory cytokins including TNF the thought has been that giving patients TNF inhibitors may be beneficial. This trial looked at 63 patients (mean age 66 years, median survival ~160 days) with 'incurable' cancers, decent performance statuses (ECOG 2 or less), likely survival greater than 3 months per the referring oncologist, more than a '2.27 kg' weight loss in 2 months, and who perceived weight loss as a problem. They were randomized to 25 mg subcutaneously etanercept or placebo for up to 24 weeks, with a primary outcome of proportion of patients who had a 10% weight gain. The use of other appetite stimulants was discouraged but not controlled (a similarly small proportion of patients used megestrol in both groups). The authors did a power analysis, and also note that the study was stopped early due to poor accrual, and it's fair to say that the study was under-powered.

Despite being under-powered the results were completely unimpressive: no one gained 10% of weight in either group, and etanercept had no other statistically significant effect on weight overall, quality of life, appetite, or survival. Side effects weren't too different either. (Curiously, rates of anemia and thrombocytopenia were lower in the treatment arm, and the authors wonder if the TNF blockade was affecting those processes.)

So - another negative controlled trial for cancer cachexia. Given the complextiy of the syndrome, I'm wondering if single agent trials will ever be effective. Maybe it requires inhibition of multiple cytokines simultaneously.... To show that, however, would be astonishingly complex (and risky with all the polypharmacy, etc.). One wonders if 'curing cancer' will be easier in the long run....

I've made my skepticism about the benefit of appetite stimulants in advanced cancer known on this blog before, so I'll point out it's a coincidence and not me being opinionated that the same issue has a case series and review warning of adrenal insufficiency & hypogonadism in cancer patients taking megestrol acetate.

Cancer also has an article about prognosis and pathologic fractures. The data come from retrospective analyses of data from 3 controlled trials looking at zoledronic acid to reduce skeletal complications for cancer patients with bone metastases. This study, and presumably the 3 trials, were funded by Novartis (the manufacturer of zoledronic acid). It's quite a complicated analysis - limited by different patient populations in different trials, and difficulty in comparing prognoses between those who had fractures and those that didn't (e.g. the concern that those who had fractures were sicker at baseline making it inappropriate to compare their survival with those that didn't have fractures). Anyway, their analysis suggests that for breast cancer and myeloma pathologic fractures are associated with worse prognosis (but not for lung cancer - prognosis was poor all around for this group and not modulated by sustaining a fracture). So, for you prognosis junkies out there (ahem, Christian), there you go.

The article has a 'zoledronic acid hooray' tone to it, and the concluding language (as well as the abstract) intimate that preventing fractures will save lives (and so, by extension, will zoledronic acid). This conclusion doesn't seem supported by this analysis; the conservative interpretation would be that fractures are associated with worse survival, not that they cause earlier death, and I found the conclusion pretty frustrating. Anyway, it's not as if the prevention of a fracture is an outcome whose importance is debatable.

And finally there's a review on psychiatric disorders in advanced cancer. It's a general, practical review of the prevalence and treatment of various psychiatric problems in cancer (depression, anxiety, even personality disorders): another good one for the teaching file. What stopped me in my tracks were these sentences about the role of the physician:

"By listening, the physician provides the patient a chance to be heard and understood, explore fears and concerns, mourn losses, articulate hopes and final wishes, and share the unique meaning that illness has for each individual. Listening reminds the patient that the physician is not too scared, too tired, or too busy to be present, and demonstrates that the patient, who may be diminished by illness, is still valued."

I wish I wrote that.

There's also a piece I just stumbled across in a recent Canadian Journal of Public Health about public (mis-)understanding of concepts like euthanasia and treatment withdrawal. I've only (yet) been able to read this paper in abstract form (it's from Quebec & it's unclear if these were French speakers in the survey) but its findings are supportive of the idea that at least part of public support for euthanasia is due to confusing it with withdrawing life-prolonging treatment. I know I've had to correct misunderstandings many of my well-educated and worldly friends and family members have had about this. A quote:

"Support for euthanasia (69.6%) was less prevalent than for treatment withdrawal (85.8%). Respondents who failed to distinguish between euthanasia and treatment withdrawal or withholding treatment in hypothetical scenarios were more likely to support euthanasia in public opinion poll questions. Furthermore, there is a significant relationship between opinions about the acceptability of euthanasia and inaccurate knowledge of the nature of euthanasia."

Finally, and only a little off-topic, NEJM has a brief and fascinating look at the history of stem cell transplantation as this is (sort of) the 50th anniversary of the technique (free full text here).

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